title: Activation of MRTF-A-dependent gene expression with a small molecule promotes myofibroblast differentiation and wound healing.
abstract: Myocardin-related transcription factors (MRTFs) regulate cellular contractility and motility by associating with serum response factor (SRF) and activating genes involved in cytoskeletal dynamics. We reported previously that MRTF-A contributes to pathological cardiac remodeling by promoting differentiation of fibroblasts to myofibroblasts following myocardial infarction. Here, we show that forced expression of MRTF-A in dermal fibroblasts stimulates contraction of a collagen matrix, whereas contractility of MRTF-A null fibroblasts is impaired under basal conditions and in response to TGF-β1 stimulation. We also identify an isoxazole ring-containing small molecule, previously shown to induce smooth muscle α-actin gene expression in cardiac progenitor cells, as an agonist of myofibroblast differentiation. Isoxazole stimulates myofibroblast differentiation via induction of MRTF-A-dependent gene expression. The MRTF-SRF signaling axis is activated in response to skin injury, and treatment of dermal wounds with isoxazole accelerates wound closure and suppresses the inflammatory response. These results reveal an important role for MRTF-SRF signaling in dermal myofibroblast differentiation and wound healing and suggest that targeting MRTFs pharmacologically may prove useful in treating diseases associated with inappropriate myofibroblast activity.
authors.affiliation: Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642.
authors.forename: Lissette S
authors.initials: LS
authors.lastname: Velasquez
authors.forename: Lillian B
authors.initials: LB
authors.lastname: Sutherland
authors.forename: Zhenan
authors.initials: Z
authors.lastname: Liu
authors.forename: Frederick
authors.initials: F
authors.lastname: Grinnell
authors.forename: Kristine E
authors.initials: KE
authors.lastname: Kamm
authors.forename: Jay W
authors.initials: JW
authors.lastname: Schneider
authors.forename: Eric N
authors.initials: EN
authors.lastname: Olson
authors.forename: Eric M
authors.initials: EM
authors.lastname: Small
mesh_terms: D000737:Androstenols / Q000494:pharmacology; D000818:Animals; D002454:Cell Differentiation; D020405:Dermis / Q000293:injuries* / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D051379:Mice; D058628:Myofibroblasts / Q000378:metabolism* / Q000473:pathology; D015534:Trans-Activators / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D014945:Wound Healing
chemical_list: D000737:Androstenols; C511173:Mrtfa protein, mouse; D015534:Trans-Activators; D053773:Transforming Growth Factor beta1; C017039:azastene
keywords: MAP kinase signaling; dermal injury; fibrosis; granulation tissue